Nature Sub-Journal: Discovery of gene mutations that cause gradual freezing, siRNA is expected to be a treatment

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, commonly known as gradual freezing disease.
The upper and lower motor neurons of the patient are affected, resulting in muscle weakness, muscle atrophy, tremor, and spasm in the muscles innervated by the neurons.
The clinical symptoms, the course of the disease are mostly progressive development, and the final death is often due to respiratory paralysis.

The famous physicist Hawking suffered from amyotrophic lateral sclerosis (ALS).

Most cases of ALS are sporadic, and the cause is still not fully understood.

With clinical studies linking single-gene mutations directly to the disease, people have gained important insights into key drivers of ALS.

On May 31, 2021, researchers from the National Institutes of Health, Bethesda University of Health Sciences Unified Service and other units published in the top international medical journal Nature Medicine the title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis Clinical report.

The report found that children with severe early-onset amyotrophic lateral sclerosis (ALS) have a rare mutation in the SPTLC1 gene, which encodes a key metabolic molecule responsible for the production of a class of sphingolipids.
Lipids.

This report reveals a single disease-causing gene for early-onset ALS and a new metabolic-related molecular pathway that may cause neurodegeneration in other types of the disease.

Carsten Bönnemann of the Uniformed Services University of Health Sciences in Bethesda, Maryland, USA, and others sequenced the genomes of 9 patients from 7 families with severe early-onset ALS.

The authors found a set of rare mutations in a single gene (SPTLC1), which encodes a component of an enzyme involved in lipid metabolism.

Experiments have found that these newly discovered disease-causing mutations in ALS lead to uncontrolled production of sphingomyelin and accumulation in human motor neurons-it is this type of neuron that is particularly degraded in this disease.

This clinical study of SPTLC1 variants in children with ALS not only describes a set of rare single-gene mutations behind an aggressive early-onset ALS, but also shows that direct metabolic disorders are a pathogenic factor in the progression of the disease.

In addition, the research team also used siRNA for experiments to try to suppress the newly discovered mutant SPLTC1 gene.

The research team's experiments on patients' skin cells showed that siRNA can not only reduce the expression level of SPLTC1 gene, but also restore sphingomyelin to normal levels.

These preliminary results indicate that precise gene silencing strategies can be used to treat patients with this type of frostbite.

The research team is also exploring other ways to reduce the accumulation of sphingomyelin in human motor neurons.
The ultimate goal is to transform these ideas into effective treatments for patients who currently have no treatment options.

Link to the paper: https:// Open for reprint